KIR3DS1 is presumed to be an NK cell activation receptor. The gene has many ( greater than 40) inhibitory alleles, known as KIR3DL1. Various KIR3DL1 subtypes have been shown to interact directly with HLA-I proteins with the Bw4 public epitope. Regardless of its similarity to KIR3DL1, and its established role in HIV disease, KIR3DS1 has only recently been shown to be expressed on NK cells and no ligand has been described. Toward an understanding of KIR3DS1 ligand binding we developed a reporter system for the engagement of KIR3DS1. The system uses KIR3DS1 fused to the T cell receptor zeta signaling chain. In addition, we have established HLA Bw4 (B5701) expressing cell lines. These cell lines are infected with lentiviral vectors and combined with the reporter line. Thus far, lentiviral infection does not result in the activation of the KIR3DS1 reporter system. In addition, we have induced stress in these Bw4 expressing cells before combining them with the reporter cells. We also have identified key residues of KIR3DS1 that do not exist in KIR3DL1. Through mutagensis we have shown that W138 of KIR3DS1 is critically involved in the lack of recognition of HLA-Bw4 by KIR3DS1. Reversion of W138 to G found in KIR3DL1 confers Bw4 binding without affecting the expression or antibody recognition of the receptor.